Field of the Disclosed Subject Matter
The present disclosed subject matter relates to systems and methods for detection of particles, such as protein monomers, protein aggregates and foreign particles, which can be found in a liquid beneficial agent.
Description of Related Art
Beneficial agents for diagnostic and therapeutic uses typically are available in liquid form. Such liquid beneficial agents can be biologics, small molecule pharmaceuticals, nutritional products, or combinations thereof. It is often helpful, if not necessary, to inspect such liquid beneficial agents to ensure particles, contaminants, aggregates, or other undesirable materials are not present. Preferably, such inspection occurs during manufacture and packaging. Additionally, however, such inspections may be helpful after shipping, during storage, and/or prior to use.
One of the most common routes of administration for liquid beneficial agents is by injection, including intravenous, subcutaneous or intramuscular injection. For example, a syringe containing the liquid beneficial agent can be used for the injection, which typically is carried out by medical personnel or other health care providers. In certain instances, a patient is trained in the use of the syringe to allow for self-injection. Moreover, certain medications are formulated in pre-filled syringes for patient use, to avoid the need for the patient to fill the syringe. Such pre-filled syringes can be packaged in an automatic injection device, which provides an easier-to-use and more rapid delivery system for the beneficial agent.
As noted, it can be helpful or necessary to inspect the contents of the pre-filled syringe to ensure quality and safety of the beneficial agent. For example, it is often desirable to inspect biological drugs for protein aggregates. When biological drugs are formulated at relatively high concentrations or volumes, the risk of generating molecular aggregates can increase. These aggregates can range in size from a few nanometers to many microns.
Naked eye inspection of the contents of a syringe is a recognized and generally acceptable method used for quality control. However, naked eye inspection can be subjective and can lack the sensitivity to detect low concentrations of particles or subvisible particles. Certain commercial systems have been developed with automated operation and relatively high sample throughput inspection of syringe contents for particles. Some commercially available systems, for example Seidenader VI series and Brevetti K15 systems, can provide high-throughput syringe inspection noninvasively, but can only effectively detect “visibles” (i.e., particles larger than about 10-25 microns). In contrast, some known experimental research lab systems can provide higher resolution particle detection, but these systems rely on manual and/or invasive techniques that render relatively low sample throughput. For example, dynamic light scattering (DLS) can provide a molecular resolution of about 1 nm, and Nanoparticle Tracking Analysis (NTA), used in systems marketed by NanoSight Ltd., can image particles as small as about 20 nm. However, these invasive techniques have a relatively low throughput compared to other methods.
U.S. Patent Application Publication No. 2010/0102247 to Arvinte describes a digital scanner-based particle detection technique for improved sensitivity over commercial systems. However, such a system can be limited by the resolution of the scanner and relatively low contrast, and thus can be ineffective at detecting low concentrations of subvisible particles (for example, below about 1 to 10 microns in size).
As such, there remains a need for systems and methods that can noninvasively provide high-throughput, high-sensitivity evaluation of liquid beneficial agents, particularly in pre-filled syringes, to detect the presence of sub-micron particles, even in low concentrations.